Abstract
Pulmonary hypertension (PH) is a progressive and serious disease, where exacerbated inflammatory response plays a critical role. Isoliquiritigenin (ISL), an important flavonoid isolated from Glycyrrhizae radix, exhibits a wide range of pharmacological actions including anti-inflammation. Previously we found ISL alleviated hypoxia-induced PH; in the present study, to extend this, we evaluated the effects of ISL on monocrotaline (MCT)-induced PH and the relevant mechanisms. Rats received a single intraperitoneal injection of MCT, followed by intragastric treatments with ISL (10 mg/kg/d or 30 mg/kg/d) once a day for 28 days. The MCT administration increased the right ventricular systolic pressure (RVSP) (p < 0.001), the median width of pulmonary arteries (p < 0.01), and the weight ratio of the right ventricular wall/left ventricular wall plus septum (Fulton index) (p < 0.01) in rats; however, these changes were inhibited by both doses of ISL (p < 0.05). In addition, treatment with ISL suppressed the upregulated production of serum interleukin-6 (p < 0.01) and tumor necrosis factor-α (p < 0.05) by MCT and reversed the increases in the numbers of proliferating cell nuclear antigen (PCNA)-positive cells (p < 0.01) in the medial wall of pulmonary arteries. In in vitro experiments, ISL (10 μM, 30 μM, and 100 μM) inhibited excessive proliferation of cultured primary pulmonary artery smooth muscle cells (PASMCs) (p < 0.05, p < 0.01, and p < 0.001) in a dose-dependent manner and prevented an increase in the expressions of PCNA (p < 0.01) and phospho-Akt (p < 0.05) in PASMCs induced by hypoxia. These results suggest that ISL can attenuate MCT-induced PH via its anti-inflammatory and antiproliferative actions.
Highlights
Pulmonary hypertension (PH) is a progressive and severe disease characterized pathophysiologically by increased pulmonary pressure, pulmonary artery structural remodeling, and right ventricular hypertrophy and leads to death [1, 2]
In agreement with the right ventricular systolic pressure (RVSP) results, MCT induced a significant elevation of the Fulton indices [F(3, 28) = 4.59, p < 0.01, saline group vs. MCT group, p < 0.01], which was blocked by both doses of ISL treatment (MCT group vs. MCT+ISL10, p < 0.05; MCT group vs. MCT+ISL30, p < 0.05) (Figure 1(b))
MCT-induced pulmonary artery remodeling was indexed by WT% and WA% of pulmonary arteries
Summary
Pulmonary hypertension (PH) is a progressive and severe disease characterized pathophysiologically by increased pulmonary pressure, pulmonary artery structural remodeling, and right ventricular hypertrophy and leads to death [1, 2]. There are three major classes of drugs, prostaglandins, phosphodiesterase inhibitors, and endothelin receptor antagonists available to treat PH, but they all present limited effectiveness and even produce unwanted consequences such as dysregulated pulmonary vasoconstriction response and worsened gas exchange [3, 4]. There is an urgent need to develop new agents that are more effective and less adverse in treating PH. There are several types of animal PH models including monocrotaline (MCT)-induced rat PH, which pathophysiologically mimic human PH and help screen new chemical candidates for the treatment of PH. Studies have shown that a single dose of MCT can elicit the typical PH pathophysiologies in rat cardiopulmonary system, which share similar processes with those in human PH. MCT administration engenders a persistent elevation of pulmonary vascular
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